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Reduction in Glutathione Peroxidase 4 Increases Life Span Through Increased Sensitivity to Apoptosis

¹ Department of Cellular and Structural Biology, and ² Barshop Institute for Longevity and Aging Studies, the University of Texas Health Science Center at San Antonio.
³ Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio.
⁴ Departments of Genetics & Medical Genetics, University of Wisconsin-Madison.
⁵ Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee.
⁶ Department of Pathology, University of Washington, Seattle.

Address correspondence to Arlan Richardson, PhD, Barshop Institute for Longevity and Aging Studies, 15355 Lambda Drive, San Antonio, TX 78245-3207. E-mail: richardsona{at}uthscsa.edu

Glutathione peroxidase 4 (Gpx4) is an antioxidant defense enzyme that plays an important role in detoxification of oxidative damage to membrane lipids. Because oxidative stress is proposed to play a causal role in aging, we compared the life spans of Gpx4 heterozygous knockout mice (Gpx4^+/– mice) and wild-type mice (WT mice). To our surprise, the median life span of Gpx4^+/– mice (1029 days) was significantly longer than that of WT mice (963 days) even though the expression of Gpx4 was reduced approximately 50% in all tissues of Gpx4^+/– mice. Pathological analysis revealed that Gpx4^+/– mice showed a delayed occurrence of fatal tumor lymphoma and a reduced severity of glomerulonephritis. Compared to WT mice, Gpx4^+/– mice showed significantly increased sensitivity to oxidative stress-induced apoptosis. Our data indicate that lifelong reduction in Gpx4 increased life span and reduced/retarded age-related pathology most likely through alterations in sensitivity of tissues to apoptosis.